Three-Weekly Doses of Azithromycin for Indigenous Infants Hospitalized with Bronchiolitis: A Multicentre, Randomized, Placebo-Controlled Trial

Abstract

BackgroundBronchiolitis is a major health burden in infants globally, particularly among Indigenous populations. It is unknown if 3 weeks of azithromycin improve clinical outcomes beyond the hospitalization period. In an international, double-blind randomized controlled trial, we determined if 3 weeks of azithromycin improved clinical outcomes in Indigenous infants hospitalized with bronchiolitis.MethodsInfants aged ≤24 months were enrolled from three centers and randomized to receive three once-weekly doses of either azithromycin (30 mg/kg) or placebo. Nasopharyngeal swabs were collected at baseline and 48 h later. Primary endpoints were hospital length of stay (LOS) and duration of oxygen supplementation monitored every 12 h until judged ready for discharge. Secondary outcomes were: day-21 symptom/signs, respiratory rehospitalizations within 6 months post-discharge and impact upon nasopharyngeal bacteria and virus shedding at 48 h.ResultsTwo hundred nineteen infants were randomized (n = 106 azithromycin, n = 113 placebo). No significant between-group differences were found for LOS (median 54 h for each group, difference = 0 h, 95% CI: −6, 8; p = 0.8), time receiving oxygen (azithromycin = 40 h, placebo = 35 h, group difference = 5 h, 95% CI: −8, 11; p = 0.7), day-21 symptom/signs, or rehospitalization within 6 months (azithromycin n = 31, placebo n = 25 infants, p = 0.2). Azithromycin reduced nasopharyngeal bacterial carriage (between-group difference 0.4 bacteria/child, 95% CI: 0.2, 0.6; p < 0.001), but had no significant effect upon virus detection rates.ConclusionDespite reducing nasopharyngeal bacterial carriage, three large once-weekly doses of azithromycin did not confer any benefit over placebo during the bronchiolitis illness or 6 months post hospitalization. Azithromycin should not be used routinely to treat infants hospitalized with bronchiolitis.Clinical trial registrationThe trial was registered with the Australian and New Zealand Clinical Trials Register: Clinical trials number: ACTRN1261000036099.

Further clinical trials on macrolides for bronchiolitis in infants are unnecessary

“…However, we wish to highlight that 5 RCTs have already been published evaluating different doses and durations of macrolides for those hospitalized with bronchiolitis. [2][3][4][5][6] Nonetheless, just 1 small RCT comprising 30 infants 2 was cited as the ''only previous trial for the prevention of post-RSV wheezing.'' 1 This Turkish study reported clinically improved outcomes during hospitalization and contrasts with the other 4 trials (range, 71-219 subjects) in which no clinical benefits were detected in infants from The Netherlands, Brazil, Australia, and New Zealand.…”

“…1 This Turkish study reported clinically improved outcomes during hospitalization and contrasts with the other 4 trials (range, 71-219 subjects) in which no clinical benefits were detected in infants from The Netherlands, Brazil, Australia, and New Zealand. [3][4][5][6] However, only 3 of the 5 published RCTs reported clinical data beyond the hospitalization period. 2,5,6 The Turkish study suffered an attrition rate of 30%, leaving only 21 infants to be followed for the next 6 months, with 1 of the 12 infants allocated 3 weeks of daily clarithromycin and 4 of the 9 treated with placebo requiring a respiratory illness readmission, a result that did not reach statistical significance.…”

“…[3][4][5][6] However, only 3 of the 5 published RCTs reported clinical data beyond the hospitalization period. 2,5,6 The Turkish study suffered an attrition rate of 30%, leaving only 21 infants to be followed for the next 6 months, with 1 of the 12 infants allocated 3 weeks of daily clarithromycin and 4 of the 9 treated with placebo requiring a respiratory illness readmission, a result that did not reach statistical significance. 2 The other 2 studies from Australia and New Zealand involved a combined total of 316 infants (89% Indigenous infants, 44% RSV) who received single large once-weekly doses of azithromycin on either 1 or 3 occasions, doses that were equivalent to 7-day 6 or 3-week 5 treatment, respectively.…”

“…Between-group differences at the day-21 clinical review were also not significant, and persistent wheezing was reported in 11% of the infants in the azithromycin group compared with 10% of the infants in the placebo group. 5 With respect to respiratory readmissions, data from both studies revealed that 101 infants were readmitted (azithromycin 57, placebo 44), of whom 70% were admitted for wheezing episodes. 5,6 Thus, azithromycin did not provide immediate or longer-term (6-months) clinical benefits in bronchiolitis for infants regarded as being at high risk of disease severity and readmission for respiratory illnesses.…”

Viral/bacterial respiratory tract co-infections in children

“…Randomised controlled trials of antibiotic treatments for paediatric bronchiolitis, most commonly caused by RSV, have found limited effect on clinical outcomes like length of hospitalisation stay, despite reductions in bacterial load in the URT (72)(73)(74). Thus, there are concerns that in many paediatric ARI cases, antibiotic prescriptions are unjustified and potentially contribute to the development of antibiotic resistance (70).…”